Osteoporosis is an enormous public health problem. Recent estimates indicate that about 44 million US women and men aged 50 years and older have osteoporosis or low bone mass, resulting in 1.5 million fractures per year, including 300,000 hip fractures, 700,000 spine fractures, 250,000 forearm fractures, and 250,000 fractures at other sites. While traditionally considered a disease of women, men also develop osteoporosis. Thus, at age 50, the lifetime risk of an osteoporotic fracture in women is 40%, and the comparable figure for men is 13%. Given the scope of this problem and the projected increase in the prevalence of this disease as the population ages, rational approaches to prevention and treatment depend critically on gaining a better understanding the pathogenesis of this disorder, as well as assessing its impact in the community. Work over the previous funding cycle has now identified estrogen (E) deficiency as a key factor in the development of age-related bone loss not only in women, but also in men; hence, a theme common to all projects is E regulation of bone metabolism. As in the past, the major strength of our group is to bring together diverse disciplines into synergistic interactions, and the present application spans the spectrum from population-based epidemiology studies, intensive studies in the clinical research center, animal studies using novel mouse knock out models, and basic molecular studies using state-of-the-art proteomics technology. This is accomplished through five Projects and an Administrative and Biostatistics Core: "Pathophysiology of Osteoporosis in Aging Men" and "Pathophysiology of Osteoporosis in Aging Women" utilize intensive studies in the clinical research center in men and women, respectively; "Risk Factors for Hip Fractures Among the Elderly" utilizes the resources of the Rochester Epidemiology Project in population-based epidemiology studies; "Estrogen Receptor Coactivators and Bone Metabolism" focuses on novel mouse knock out models with defects in E action; and "Actions of Estrogen Receptor Coregulators in Osteoblasts" proposes to dissect E action in bone cells at a molecular level. Collectively, these studies strive to provide a comprehensive assessment of the pathogenesis and clinical impact of this important disorder.